Portuguese ScienceIn collaboration with the National Agency for Scientific and Technologic Culture (Ciência Viva)
Financed by the Fundação para a Ciência e Tecnologia (FCT)

A new prognostic tool for gastric carcinomas? (and maybe other cancers) (05/2005)

A new way to identify gastric carcinoma patients with high probability of develop a more aggressive form of disease has just been described on the June issue of the journal Glycobiology1.

Researchers have found that the peptide sequence(a) of mucins - a group of proteins expressed by epithelial cells -seemed to be directly associated with the expression of tumour markers linked to very severe gastric carcinomas. Because peptide sequences are genetically determined, not only this discovery can allow doctors to predict which gastric carcinoma patients are more at risk, but also, one day, might help to predict the illness even before the appearance of signs. Furthermore, mucins are not limited to gastric carcinomas but are also found in a multitude of other cancers what makes the discovery even more exciting.

Mucins are large glycosylated (meaning that they have several sugars attached) proteins found on various epithelial cells around the body. These proteins perform several important functions from acting as molecular barriers, protecting epithelial cells from adverse environments, to the reception and coordination of signals involved in growth, differentiation, proliferation and even cellular death. Interestingly, mucins are also believed to participate in tumour development including the formation of metastasis, which are responsible for disease spread. In fact, during cancer, the expression and number of mucins increases, while their glycosylation suffer aberrant changes that lead to the uncovering of previously hidden structures - named tumour-associated carbohydrate antigens or TACAs – which seem to be directly involved in cancer progression. The most common TACAs described are Tn, sialyl-Tn, and T (Thomsen-Friedenreich), and analysis of their expression in cancerous cells is helping scientists characterising tumour as the antibodies against TACAs, already widely used as diagnostic tools to several types of cancers, prove.

Filipe Santos-Silva, Ana Fonseca, Michael Anthony Hollingsworth and colleagues from the University of Porto, Portugal and the University of Nebraska Medical Center, USA while trying to understand, in gastric carcinomas, the mechanism behind TACAs expression (and consequently behind cancer development) decided to analyse the peptide sequences of MUC1, a mucin commonly found altered in this type of cancer, trying to see if these could be correlated with disease prognosis. It is known that “normal” glycosylation in mucins is determined by their peptide sequence and the team of scientists hypothesized, that maybe MUC1 aberrant glycosylation in cancerous cells and subsequent TACAs’ expression, could be traced back to the same reason (changes in a particular peptide sequence).

Santos-Silva, Fonseca, Holingsworth and colleagues studied cells from 77 gastric carcinoma patients and found that the length of certain peptides sequences found in MUC1 were in fact directly associated with Thomsen-Friedenreich tumour marker expression. High levels of this tumour marker correlate, in gastric carcinomas, with the most aggressive cases of disease, and to be able to identify higher risk individuals can be crucial to their chances of survival. In order to confirm these results gastric carcinoma cells were manipulated into express MUC1 with different peptide lengths, and again, it was possible to identify which lengths of specific peptide sequences resulted in high levels of Thomsen-Friedenreich tumour marker.

Santos-Silva, Fonseca, Holingsworth and colleagues’ work seems to show that the expression of molecules involved in cancer development (the TACAs) is genetically determined which opens the door for the identification of individual predispositions to, in the case of gastric carcinomas, more severe cases of disease. These results, although extremely preliminary, are nevertheless very interesting as altered mucins can be found in most cancers and to be able to predict TACAs expression by peptide length can be a crucial tool for early prognosis.

Gastric carcinoma or cancer of the stomach is the second commonest cause of cancer deaths world wide, behind only to lung cancer. Prognosis is generally very poor with only 5% of the patients surviving more than 5 years. Although the disease is less frequent in the western world, in the UK alone, this cancer kills 7,000 people per year, a number that clearly shows what serious health problem the disease is and how important new methods for early prognosis can be.